This application proposes studies to investigate mechanisms that affect cellular immune responses to HIV infection. The focus is on the role played by Nef as an immune modulator. Nef plays a crucial role in HIV pathogenesis, but the precise reason for its importance is not understood. Understanding the molecular basis for Nef's contribution to HIV pathogenesis is crucial for the development of vaccines against HIV, as well as for the development of therapeutic interventions. The proposed experiments will examine how Nef interacts with signaling molecules to regulate the expression of several key immune effector proteins. Nef regulates the expression levels of both surface CD4 and class I MHC molecules, and the loss of class I MHC molecules from the infected cell surface may be a mechanism for evasion from cytotoxic T lymphocytes (CTLs). While this may be important under certain situations, studies from several laboratories studies suggest that Nef may act through a second mechanism, independent of its effect on class I MHC expression. This mechanism could also result in "protection" of Nef-expressing target cells from CTL lysis. The investigators hypothesize that HIV Nef mediates immune evasion through the upregulation of Fas ligand (FasL) on the infected target cells. Removal of Fas-expressing activated "memory" CTL may significantly contribute to pathogenesis. This proposal will test this hypothesis, and attempt to elucidate the molecular basis for immune evasion mediated through Nef.